The tremendous potential of solving the donor organ shortage with xenotransplantation of genetically engineered pigs is shadowed by the potential infection risks. Thus, if the xenotransplantation of pig tissues results in the activation of PERV viral replication, the risk of spreading this retrovirus to the human host is real, especially activated cells infiltrating a graft site under potent immunosuppression. That could result in an increased risk of leukemia or lymphoid tumors. In turn, if the transplant patient becomes infected there is also a potential of selecting and spreading a new variant of PERV adapted to the human host, first to immediate contacts and next to the public. Therefore, there is a critical need to advance our current understanding of the risk and biology of xenogeneic viral infection as part of a strategy for moving forward with clinical trials of xenotransplantation. The centerpiece for the present grant proposal is that we are the first group to clone the human receptors for PERV A. Therefore, the objectives of this proposal are to determine the expression of these receptors in human tissues as well as develop a transgenic mouse model expressing either or both the human PERV A receptors. If successful, this will be a major advance in the field allowing us to study the potential of PERV infection via the human receptor, compartmentalization, pathogenesis, viral adaptation impact of immunosuppression and risk of spread to uninfected animals. Specific Aim #I : Determine the expression of the human PERV A receptors in human tissue compartments and explore activation-induced changes in expression, cellular compartmentalization and possible functional impact of the PERV A receptors and PERV A virus in lymphocytes. Specific Aim #2: Produce transgenic mice for both human PERV A receptors (Al/A2) and determine the incidence, compartmentalization, phenotype and risk of PERV infection in this novel small animal model.